This research protocol is designed to study gene expression differentials and immunologic profile and histopatologic presentation of podoconiosis by comparing cases and controls in Ethiopia. Podoconiosis is a geochemical lymphedema of the lower limbs resulting from long term barefoot exposure to irritant red clay soils of volcanic origin. The disease imposes huge social and economic burden and affects more than 4 million individuals in tropical Africa, Central and South America, and North India. The pathologic changes in podoconiosis are still not known and the histopathologic features of the disease have not been well studied. Our recent genome-wide association study revealed that variants in HLA class II genes (HLA-DRB1, -DQB1, and -DQA1) are associated with podoconiosis, and suggests that the disease may be a Tcell mediated inflammatory condition (New Eng J Med 2012). The objectives of the present study are to investigate the immunologic profiles and gene expression differences between podoconiosis patients and healthy controls. The study will include 150 subjects consisting of 100 cases (50 early stage and 50 advanced stage), and 50 controls from Ethiopia. Anonymized discarded skin tissue samples will be obtained from excised nodules of 50 advanced stage patients that undergo nodulectomy (surgical excisions of nodules) in Bahir Dar Hospital. Punch biopsies will be obtained from affected skin tissues (epidermis and dermis) of 50 early stage podoconiosis patients that attend routine treatment in Dur-Bete Podoconiosis Center, and normal skin tissues (epidermis and dermis) of 50 control subjects undergoing orthopedic surgery of the lower legs in Bahir Dar Hospital. We will also obtain 6 mm skin tissue punch biopsies from the unaffected areas in the lower limbs of all podoconiosis patients and peripheral blood samples (PBS) from all study subjects. RNA from PBS and T cells separated from other cells will be extracted in Armauer Hansen Research Institute of Ethiopia (AHRI) and will be shipped along with skin biopsies that will be kept in liquid nitrogen to CRGGH/NHGRI. We will use RNA-seq, a high throughput RNA sequencing technology, to characterize the transcriptome by sequencing complementary DNAs (cDNAs) followed by mapping of the sequence reads to the genome. Generation of double-stranded cDNA from mRNA and quantitation of cDNA concentration will be done in our lab at NIH. Sequencing will be done by a commercial high throughput sequencing company, SeqWright (Houston, TX) an Illumina certified service provider. Immunologic profiling will be done using a FACSCalibur type flow cytometry. Analysis of data will be done using appropriate statistical programs and pipeline suites as described below. This study is expected to reveal differential gene expression between podoconiosis patients and controls. Furthermore, it will chart the evolution of gene expression signatures in podoconiosis patients through the different clinical stages of the disease. The findings could potentially lead to biomarkers that complement the clinical and genetic characteristics of the disease. The histopathological studies will provide a rich description of cutaneous and immunologic response across the spectrum of the disease. The integration of clinical, immunological, genetic, cellular and molecular characteristics of the disease will facilitate the development of a model for the natural history and pathogenesis of this neglected tropical disease.